Huntington's disease (HD) is an autosomal dominant selective degenerative disease of the brain. Little is known about the primary biochemical dysfunction, and detection occurs after irrepairable damage. Biochemical abnormalities in HD postmortem brains include low L-glutamic acid decarboxylase (GAD) activity and low gamma-anminobutyric acid decarboxylase (GABA) levels. GAD activity and GABA pools measured in fibroblast cell cultures derived from patients with HD can be used for early detection, positive diagnosis and studies leading to a biochemical comprehension of the disease. We have found differences between HD and control cell extracts with regard to GAD activity and differences in GABA pool sizes in intact cells. These studies are proposed to ensure that the observed changes are specific HD characteristics. A survey of several HD lines, normal lines, neuronal cell cultures and non-HD genetic neurological disease cell lines will be analyzed. After determining the authenticity of the alteration, experiments are proposed to characterize the defect. Kinetic analyses of GAD under normal and "stress" conditions are proposed for in vitro assays as well as in vivo, cells in culture. Uptake of amino acids and neurotransmitters by the cell cultures will be measured and compared with cells of neuronal origin. GABA catabolism will be measured. GAD will be isolated for initial studies on purified enzyme structure and functional capacities. These studies should establish basic parameters for future research on the mechanism and treatment of HD.